Based on our nonhuman primate studies, we proposed that human affective and anxiety-related psychopathology in part results from alterations in the adaptive regulation of anxiety and other emotional responses. Our studies have provided evidence for an anxious endophenotype in primates. Monkeys with this temperamental disposition are similar to extremely inhibited children that are at trisk to develop anxiety disorders in that they engage in excessive freezing behavior when confronted with a threatening situation. The rhesus monkey is ideal for this work because of similarities in brain structure and social behavior between rhesus monkeys and humans. In addition, compared to other species, rhesus monkeys have a well developed prefrontal cortex allowing for studies aimed at prefrontal-limbic interactions in relation to emotion regulation. The proposed studies will build on our previous work by systematically examining, in rhesus monkeys, the neural circuitry that mediates the regulation of long term anxiety responses. Long term anxiety responses are important because they reflect temperamental dispositions and, when extreme, are characteristic of human psychopathology. We will examine the roles of the central nucleus of the amygdala, the bed nucleus of the stria terminalis (BNST), and the orbitofrontal cortex (OFC) in mediating and regulating prolonged anxiety-related responses relevant to anxiety of affective disorders. Using behavioral, physiological, lesioning, and high resolution [18F]-flouro-2-deoxy-D-glucose microPET imaging techniques, we will test the hypotheses that the BNST has a primary role in the long term expression of freezing, or behavioral inhibition, and that the OFC is involved in the ability to terminate and.regulate anxiety responses in relation to changing environmental contexts. Elucidating the mechanisms that underlie the regulation of long term anxiety in primates will provide insights into the mechanisms underlying the pathophysiology of human affective and anxiety disorders.